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Researchers
  • Prof.  Moshe Kotler
Prof Moshe Kotler
 
Research Interests
 
The main goals of our laboratory are to elucidate the biochemical and biological processes that underline antiviral cellular defense mechanisms and the viral proteins employed to counteract these cellular defenses.  Particularly, we are studying the interaction between HIV-1 Vif and the cellular APOBEC3 proteins, and the function of the Betanodavirus B2 protein that suppresses cellular RNA interference.

Our laboratory is studying cellular deaminases, which impede the production of infectious HIV-1 particles, restrict retrotransposition and prevent acquisition of foreign genetic material.  Members of this group of cellular deaminases play important roles in antibody production and in tumorigenesis. 

HIV-1 target cells express factors belonging to the APOBEC3 (A3) protein family, mainly APOBEC3G (A3G) and A3F. A3 proteins are cytidine deaminases that if incorporated into HIV-1 particles induce hypermutation and inactivation of the viral genome. HIV-1 overcomes the peril of A3G and A3F by encoding the viral infectivity factor (Vif), which neutralizes these cellular proteins by mediating their degradation.
 
Research Projects
 
 
 
The interaction of Vif/APOBEC3G (A3G). Our recent results show that Vif and A3G are incorporated into HIV-1 particles and that Vif inhibits the enzymatic activity of A3G in the pre-integration complex following virus penetration to target cells. Moreover, dissection of Vif functional domains revealed that two Vif derived peptides inhibit the enzymatic activity of A3G.
  
In addition to the direct Vif activity in neutralizing A3G and A3F, we found that Vif is secreted from HIV-1 infected cells, penetrating into naïve B and T lymphocytes. We are testing now whether Vif enable to modulate the production of mature antibodies by these cells.
 
 
 
The mechanism by which A3G deaminates deoxycytidines in the ssDNA produced by HIV-1 reverse transcriptase. Multimeric A3G conglomerates associate with RNA molecules that are present in the cytoplasm of HIV-1 target cells. We suggest that A3G is incorporated into virions as multimeres bound to the viral RNA and disassemble into multiple monomeric mutator units following interaction with ssDNA molecules synthesized by reverse transcriptase.
 
The regulation of A3G expression in primary lymphocytes: We are testing the possibility that estrogen enhances A3G expression in lymphocytes, reducing their sensitivity to HIV-1 propagation.
 
 
 
The function of A3G in protecting the cells genome against deleterious effect of double strand brakes (DSB). A3G accumulation at the DSB foci appeared in cancerous lymphocytes following commencement of ionizing radiation (IR). A3G supports and accelerates DSB repair, rendering lymphoma cells IR resistant. We are looking now for A3G inhibitors, which could enhance the sensitivity of lymphomas to radiotherapy.
 
A3G is predominantly a cytoplasmic protein. However it penetrates the cell nuclei following UV and IR irradiation. It is our interest to reveal the mechanisms and the cellular proteins enabling A3G entrance to the nuclei.
 
 
 
 
 
 
Nervous necrosis virus (NNV) is a member of the Betanodavirus. The genome of the members of this family consists of two positive RNA strands, which yield three proteins: capsid, RNA polymerase and B2 proteins. The B2 protein prevents cleavage of virus-derived double-stranded RNAs (dsRNAs) by Dicer and subsequent production of small interfering RNA (siRNA), which would otherwise induce an RNA-silencing response against the virus. We are studying now the mechanism by which NNV B2 protein binds dsRNA. To this end, we are assessing the activity of B2 and mutated B2 proteins in fish and mammalian cells and investigating the interaction domains responsible for dsRNA binding. We expect the results of this study will be instrumental in production anti NNV vaccine and instrumental in studying the production of small interfering RNA (siRNA) molecules.
 
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Lab Members  
Prof  Moshe Kotler ​Dr Elena Britan Rosich
Prof. Moshe Kotler
Lab: +97226757300
Cell: +972504332176
Dr. Elena Britan – Rosich
Lab: +97226758200
Cell: +972526379047
Elena studies Vif/Apobec3 interaction in virion and in infected cells. 
 
​Mr Roni Nowarski
​Mr Ori Cheshin
Edan Kenig
​Mr. Roni Nowarski – Ph.D student
Lab: +97226758200
Cell: +972586517222
Roni investigates the mechanisms of deamination by A3G and the involvement of A3G in double strand break repair.
​Mr. Ori Cheshin - Ph.D student
Lab: +97226758200
Cell: +972556663036
Ori is studying the penetration of A3G into the nuclei, following irradiation, and searching cellular proteins associated with the A3G.
​​Mr. Edan Kenig - Ph.D student.
Lab: +97226758200
Cell: +972506912130
Edan is defining the A3G Biochemical activity and its role as an Epigenetic factor
 
Diana Emili
Nadia Gutkovitch Or Faigenbaum
Mrs. Diana Emili - Ph.D student
Lab: +97226758200
Cell: +972542377321
Diana showed that Vif is secreted from Infected cells and looking new Vif function in naïve cells.
​Mrs. Nadia Gutkovitch - Ph.D student.
Lab: +97226758200
Cell: +972549246922
In order to learn the mechanism of A3G Activity she is using A3G mutants which unable to form dimers or multimeres.
Mr. ​Or Faigenbaum - Ph.D student
Lab: +97226758200
Cell: +972544980090
Or is studying the functions of the NNV B2 protein in counteracting the host antiviral innate immunity.
 
 
Open Positions
 
We are always looking for talented PhD students and Post-docs.  
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Patents  
Patent 2269: Novel Vid Derived HIV Protease Inhibitors. PTC/US/98/1037
 
Patent 2703: Immunizing Fish Against Viral Infection by Dr. M. Kotler, Dr. Y. Bejerano, A. Benet, N. Chen, M. Hutoran and A. Ronen. PCT/IL03/01097,
 
Patent 2712: Method of Detecting Drug Resistance by Drs. L. Alfonta, I. Blumenzweig, M. Zayats, L. Baraz, M. Kotler and I. Willner. PCT/IL03/00790
 
Patent 2870: Peptides, Antibodies and Compositions Containing same Useful for Reating and Detecting HIV Virus Infection. Yissum Ref. No. 2870.00. Dr. M. Kotler, Dr. L. Baraz, M. Hutoran and I. Britan. PCT/IL2005000531.
 
Patent 3132: A Virus Spotlighted by an Autonomous DNA Machine. PCT/IL2007/000794:
 
Patent 3155: Compositions and Methods for Inhibiting HIV-1 Replication And Integrase Activity.  PCT/IL2007/001321.
 
Patent 3179: Compositions and Method for Inhibiting HIV-1 Replication and Intergrase Activity.  PCT/IL2007/001516
 
Patent 3304: Inhibition of Infectious HIV-1 Production by Synthetic Peptides US 28.1.2008 61/023,902, US 20/02/2008 61/029,928
 
Patent 3416: Novel Macrocyclic Molecules for Treating or Preventing HIV Infection. US 27/08/2008 61/092,293
 
Patent: Intervention in Cancer Treatment by Inhibition of the Cellular APOBEC3 Proteins. US 02/2011 
 
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 Supports and Collaborations
 
 
Our studies on the APOBEC3 are supported by NIH grant. The study is carried out in collaboration with R.S. Harris (Minnesota, USA).
 
The Vif study is supported by the Ministry of Health – Israel
 
The selection of Vif inhibitor is supported by BSF in collaboration with Assaf Friedler.
 
The research on NNV B2 protein is supported by the Ministry of Agriculture and Rural Development –Israel.
 
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CV 
Education:
 
1960-1963
B.Sc. Microbiology and Botany, Hebrew University, Jerusalem, Israel.
 
1963-1964
M.Sc. Botany, Hebrew University, Jerusalem, Israel.
 
1964-1968
Ph.D. Oncology, Weizmann Institute, Rehovot, Israel. Subject: Development of reticulum cell neoplasm in SJL/J mice.
 
Employment:
 
1968-1970
Research Associate, Department of Virology, McArdle Laboratory of Cancer Research, Madison, WI (with Dr. H. M. Temin).
 
1970-1971
Research Associate, Department of Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1972-1977
Lecturer, Department of Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1977-1978
Senior Lecturer, Department of Molecular Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1978-1979
Associate Professor, Department of Cancer Research, School of Medicine, Tufts University, Boston, MA (with Dr. J. M. Coffin).
 
1979-1982
Senior Lecturer, Department of Molecular Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1982-1984
Chairman, Microbiology Studies Program, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1982-1986
Senior Lecturer, Department of Molecular Genetics, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1986-1995
Associate Professor, Department of Molecular Genetics, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1986-1987
Visiting Scientist, Department of Molecular Oncology, Roche Institute of Molecular Biology, Nutley, NJ.
 
1987
Visiting Scientist, Fox Chase Institute for Cancer Research, Philadelphia, PA.
 
1990-1991
Visiting Scientist, National Cancer Institute, Frederick Cancer Research Facility, Frederick, MD.
 
1994
Chairman, Department of Molecular Genetics, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
1995-present
Full Professor, Department of Immunology and Pathology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
 
Professional Society Membership and Honors:
 
1973
American Society of Microbiology Faculty Prize in honor of A. Back.
 
1982-1984
Chairman, Microbiology Studies Program, Hebrew University- Hadassah Medical School, Jerusalem, Israel.
 
2006
Prize for applicative research
 
 
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